Direct Observation and Analysis of the Halo-Amino-Nitro Alkane Functional Group

Abstract

Conventional amide synthesis is a mainstay in discipline-spanning applications, and it is a reaction type that historically developed as a singular paradigm when considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis (UmAS) exploits the unique properties of an a-halo nitroalkane in its reaction with an amine to produce an amide. The ‘‘umpolung’’ moniker reflects its para- digm-breaking C–N bond formation on the basis of evidence that the nucleo- philic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino- nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct obser- vation of a HANA, its conversion thermally to an amide functionality, and quan- titative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation.